Cystic fibrosis (CF) is a disease caused by mutations in the cftr gene which induces defects in the CFTR protein, its production and/or its function. Cystic fibrosis is the most common fatal genetic disease in humans, and affects ˜0.04% of white individuals. For example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective gene without apparent ill effects; moreover subjects bearing a single copy of the gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.
In cystic fibrosis patients, mutations in endogenous respiratory epithelial CFTR lead to a failure to confer chloride and bicarbonate permeability to epithelial cells in lung and other tissues, thus leading to reduced apical anion secretion and disruptions of the ion and fluid transport. This decrease in anion transport causes an enhanced mucus and pathogenic agent accumulation in the lung triggering microbial infections that ultimately cause death in CF patients.
Beyond respiratory disease, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency that result in death if left untreated. Furthermore, female subjects with cystic fibrosis suffer from decreased fertility, whilst males with cystic fibrosis are infertile.
A variety of disease causing mutations has been identified through sequence analysis of the CFTR gene of CF chromosomes. ΔF508-CFTR, the most common CF mutation (present in at least 1 allele in ˜90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1's interactions with other domains. This deletion prevents the nascent protein from folding correctly, whereby the protein in turn cannot exit the endoplasmic reticulum (ER) and being transported to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating.
Currently there are no effective therapies for cystic fibrosis patients. Therefore, there is a need for novel compounds able to modulate CFTR.